This proposal focuses on the adhesogenic responses of endothelial cells to agonists germane to sickle cell disease. The specific aims are to test the following hypotheses: 1) that thrombin and hypoxia (I/R) enhance EC adhesivity for SS RB; 2) that specific EC adhesive molecules account for increased adhesivity; and 3) that identifiable cellular mechanisms account for the increased adhesivity. Aims 1 and 2 will be studied in vitro and, using a mouse model of sickle cell disease, in vivo. The singular focus on activated endothelial cell adhesivity provides an innovative perspective to this proposal. The availability of a transgenic knockout sickle cell mouse model highly concordant with the human disease and of a state-of-the-art intravital microscopy system provide an exceptional opportunity to verify in vivo the importance of in vitro adherence phenomena. These experiments are anticipated to enhance our understanding of the molecular mechanisms of sickle erythrocyte-endothelial adherence, improve our grasp of the pathophysiology of sickle cell vasoocclusion, and expand our knowledge of endothelial cell biology. They may provide the basis for future therapeutic interventions.